This invention is in the area of methods and compositions for inhibiting the expression of VCAM-1 and, in particular, for the treatment of diseases mediated by VCAM-1, including cardiovascular and inflammatory disease.
Coronary heart disease (CHD) remains the leading cause of death in the industrialized countries. The primary cause of CHD is atherosclerosis, a disease characterized by the deposition of lipids in the arterial vessel wall, resulting in a narrowing of the vessel passages and ultimately hardening the vascular system.
Atherosclerosis as manifested in its major clinical complication, ischemic heart disease, continues to be a major cause of death in industrialized countries. It is now well accepted that atherosclerosis can begin with local injury to the arterial endothelium followed by proliferation of arterial smooth muscle cells from the medial layer to the intimal layer along the deposition of lipid and accumulation of foam cells in the lesion. As the atherosclerotic plaque develops it progressively occludes more and more of the affected blood vessel and can eventually lead to ischaemia or infarction. Therefore, it is desirable to provide methods of inhibiting the progression of atherosclerosis in patients in need thereof.
Cardiovascular disease has been linked to several causative factors, which include hypercholesterolemia, hyperlipidemia, and the expression of VCAM-1 in vascular endothelial cells.
Expression of VCAM-1
Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, including atherosclerosis, autoimmune disorders and bacterial and viral infections. Leukocyte recruitment to the endothelium is started when inducible adhesion molecule receptors on the surface of endothelial cells interact with counterreceptors on immune cells. Vascular endothelial cells determine which type of leukocytes (monocytes, lymphocytes, or neutrophils) are recruited, by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and E-selectin. In the earliest stage of the atherosclerotic lesion, there is a localized endothelial expression of VCAM-1 and selective recruitment of mononuclear leukocytes that express the integrin counterreceptor VLA-4. Because of the selective expression of VLA-4 on monocytes and lymphocytes, but not neutrophils, VCAM-1 is important in mediating the selective adhesion of mononuclear leukocytes. Subsequent conversion of leucocytes to foamy macrophages results in the synthesis of a wide variety of inflammatory cytokines, growth factors, and chemoattractants that help propagate the leukocyte and platelet recruitment, smooth muscle cell proliferation, endothelial cell activation, and extracellular matrix synthesis characteristic of maturing atherosclerotic plaque.
VCAM-1 is a mediator in chronic inflammatory disorders such as asthma, rheumatoid arthritis and autoimmune diabetes. For example, it is known that the expression of VCAM-1 and ICAM-1 are increased in asthmatics. Pilewski, J. M., et al. Am. J. Respir. Cell Mol. Biol. 12, 1-3 (1995); Ohkawara, Y., et al., Am. J. Respir. Cell Mol. Biol. 12, 4-12 (1995). Additionally, blocking the integrin receptors for VCAM-1 and ICAM-1 (VLA-4 and LFA-1, respectively) suppressed both early and late phase responses in an ovalbumin-sensitized rat model of allergic airway responses. Rabb, 11. A., et al., Am. J. Respir. Care Med. 149, 1186-1191 (1994). There is also increased expression of endothelial adhesion molecules, including VCAM-1, in the microvasculature of rheumatoid synovium. Koch, A. E. et al., Lab. Invest. 64, 313-322 (1991); Morales-Ducret, J. et al., Immunol. 149, 1421-1431 (1992). Neutralizing antibodies directed against VCAM-1 or its counter receptor, VLA-4, can delay the onset of diabetes in a mouse model (NOD mice) which spontaneously develop the disease. Yang, X. D. et al., Proc. Natl. Acad. Sci. U.S.A. 90, 10494-10498 (1993); Burkly, L. C. et al., Diabetes 43, 523-534 (1994); Baron, J. L. et al., J. Clin. Invest. 93, 1700-1708 (1994). Monoclonal antibodies to VCAM-1 can also have a beneficial effect in animal models of allograft rejection, suggesting that inhibitors of VCAM-1 expression may have utility in preventing transplant rejection. Oroez, C. G. et al., Immunol. Lett. 32, 7-12 (1992).
VCAM-1 is expressed by cells both as a membrane bound form and as a soluble form. The soluble form of VCAM-1 has been shown to induce chemotaxis of vascular endothelial cells in vitro and stimulate an angiogenic response in rat cornea. Koch, A. F. et al., Nature 376, 517-519 (1995). Inhibitors of the expression of soluble VCAM-1 have potential therapeutic value in treating diseases with a strong angiogenic component, including tumor growth and metastasis. Folkman, J., and Shing, Y., Biol. Chem. 10931-10934 (1992).
VCAM-1 is expressed in cultured human vascular endothelial cells after activation by lipopolysaccharide (LPS) and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF-xcex1). These factors are not selective for activation of cell adhesion molecule expression.
U.S. Pat. No. 5,380,747 to Medford, et al., teaches the use of dithiocarbamates such as pyrrolidine dithiocarbamate for the treatment of cardiovascular and other inflammatory diseases.
U.S. Pat. No. 5,750,351 to Medford, et al., and WO95/30415 to Emory University describe the discovery that polyunsaturated fatty acids (xe2x80x9cPUFAsxe2x80x9d) and their hydroperoxides (xe2x80x9cox-PUFAsxe2x80x9d), which are important components of oxidatively modified low density lipoprotein (LDL), induce the expression of VCAM-1, but not intracellular adhesion molecule-1 (ICAM-1) or E-selectin in human aortic endothelial cells, through a mechanism that is not mediated by cytokines or other noncytokine signals. This is a fundamental discovery of an important and previously unknown biological pathway in VCAM-1 mediated immune responses.
As non-limiting examples, linoleic acid, linolenic acid, arachidonic acid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide (15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1 or E-selectin. Saturated fatty acids (such as stearic acid) and monounsaturated fatty acids (such as oleic acid) do not induce the expression of VCAM-1, ICAM-1 or E-selectin.
The induction of VCAM-1 by PUFAs and their fatty acid hydroperoxides is suppressed by dithiocarbamates, including pyrrolidine dithiocarbamate (PDTC). This indicates that the induction is mediated by an oxidized signal molecule, and that the induction is prevented when the oxidation of the molecule is blocked (i.e., the oxidation does not occur), reversed (i.e., the signal molecule is reduced), or when the redox modified signal is otherwise prevented from interacting with its regulatory target.
Cells that are chronically exposed to higher than normal levels of polyunsaturated fatty acids or their oxidized counterparts can initiate an immune response that is not normal and which is out of proportion to the threat presented, leading to a diseased state. The oversensitization of vascular endothelial cells to PUFAs and ox-PUFAs can accelerate the formation, for example, of atherosclerotic plaque.
Based on these discoveries, a method for the treatment of atherosclerosis, post-angioplasty restenosis, coronary artery diseases, angina, small artery disease and other cardiovascular diseases, as well as noncardiovascular inflammatory diseases that are mediated by VCAM-1, was described in WO95/30415 that includes the removal, decrease in the concentration of, or prevention of the formation of oxidized polyunsaturated fatty acids including but not limited to oxidized linoleic (C18xcex949,12), linolenic (C18xcex946,9,12), arachidonic (C20xcex945,8,11,14) and eicosatrienoic (C20xcex948,11,14) acids.
Nonlimiting examples of noncardiovascular inflammatory diseases that are mediated by VCAM-1 include rheumatoid and osteoarthritis, asthma, dermatitis, and multiple sclerosis.
Hypercholesterolemia and hyperlipidemia
Hypercholesterolemia is an important risk factor associated with cardiovascular disease. Serum lipoproteins are the carriers for lipids in the circulation. Lipoproteins are classified according to their density: chylomicrons, very low-density lipoproteins (VLDL), low density lipoproteins (LDL) and high-density lipoproteins (HDL). Chylomicrons primarily participate in transporting dietary triglycerides and cholesterol from the intestine to adipose tissue and liver. VLDL deliver endogenously synthesized triglycerides from liver to adipose and other tissues. LDL transports cholesterol to peripheral tissues and regulate endogenous cholesterol levels in those tissues. HDL transports cholesterol from peripheral tissues to the liver. Arterial wall cholesterol is derived almost exclusively from LDL. Brown and Goldstein, Ann. Rev. Biochem. 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980). In patients with low levels of LDL, the development of atherosclerosis is rare.
Steinberg, et al., (N. Eng. J. Med. 1989; 320:915-924) hypothesized that modification of low-density lipoprotein (LDL) into oxidatively modified LDL (ox-LDL) by reactive oxygen species is the central event that initiates and propagates atherosclerosis. Oxidized LDL is a complex structure consisting of at least several chemically distinct oxidized materials, each of which, alone or in combination, may modulate cytokine-activated adhesion molecule gene expression. R fatty acid hydroperoxides such as linoleyl hydroperoxide (13-HPODE) are produced from free fatty acids by lipoxygenases and are an important component of oxidized LDL.
It has been proposed that a generation of oxidized lipids is formed by the action of the cell lipoxygenase system and that the oxidized lipids are subsequently transferred to LDL. There is thereafter a propagation reaction within the LDL in the medium catalyzed by transition metals and/or sulfhydryl compounds. Previous investigations have demonstrated that fatty acid modification of cultured endothelial cells can alter their susceptibility to oxidant injury, whereas supplementation with polyunsaturated fatty acids (PUFA) enhances susceptibility to oxidant injury. Supplementation of saturated or monounsaturated fatty acids to cultured endothelial cells reduces their susceptibility to oxidant injury, whereas supplementation with polyunsaturated fatty acids (PUFA) enhances susceptibility to oxidant injury.
Using reverse-phase HPLC analysis of native and saponified liquid extracts of LDL, it has been demonstrated that 13-HPODE is the predominant oxidized fatty acid in LDL oxidized by activated human monocytes. Chronic exposure to oxidized LDL provides an oxidative signal to vascular endothelial cells, possible through a specific fatty acid hydroperoxide, that selectively augments cytokine-induced VCAM-I gene expression.
Through a mechanism that is not well defined, areas of vessel wall predisposed to atherosclerosis preferentially sequester circulating LDL. Through a poorly understood pathway, endothelial, smooth muscle, and/or inflammatory cells then convert LDL to ox-LDL. In contrast to LDL, which is taken up through the LDL receptor, monocytes avidly take up ox-LDL through a xe2x80x9cscavengerxe2x80x9d receptor whose expression, unlike the LDL receptor, is not inhibited as the content of intracellular lipid rises. Thus, monocytes continue to take up ox-LDL and become lipid-engorged macrophage-foam cells that form the fatty streak.
There is now a large body of evidence demonstrating that hypercholesterolemia is an important risk factor associated with heart disease. For example, in December 1984, a National Institute of Health Consensus Development Conference Panel concluded that lowering definitely elevated blood cholesterol levels (specifically blood levels of low-density lipoprotein cholesterol) will reduce the risk of heart attacks due to coronary heart disease.
Typically, cholesterol is carried in the blood of warm-blooded animals in certain lipid-protein complexes such as chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL). It is widely accepted that LDL functions in a way that directly results in deposition of the LDL cholesterol in the blood-vessel wall and that HDL functions in way that results in the HDL picking up cholesterol from the vessel wall and transporting it to the liver where it is metabolized [Brown and Goldstein, Ann. Rev. Biochem. 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980)]. For example, in various epidemiologic studies the LDL cholesterol levels correlate well with the risk of coronary heart disease whereas the HDL cholesterol levels are inversely associated with coronary heart disease [Patton et al., Clin. Chem. 29, 1980 (1983)]. It is generally accepted by those skilled in the art that reduction of abnormally high LDL cholesterol levels is effective therapy not only in the treatment of hypercholesterolemia but also in the treatment of atherosclerosis.
Furthermore, there is evidence based on animal and laboratory findings that peroxidation of LDL lipid, such as the unsaturated fatty acid portions of LDL cholesteryl esters and phospholipids, facilitate the accumulation of cholesterol in monocyte/macrophages which eventually are transformed into foam cells and become deposited in the sub-endothelial space of the vessel wall. The accumulation of foam cells in the vessel wall is recognized as an early event in the formation of an atherosclerotic plaque. Thus it is believed that peroxidation of LDL lipid is an important prerequisite to the facilitated accumulation of cholesterol in the vessel wall and the subsequent formation of an atherosclerotic plaque. For example, it has been shown that monocyte/macrophages take up and degrade native LDL at relatively low rates and without marked accumulation of cholesterol. In contrast, oxidized LDL is taken up by these monocyte/macrophages at much higher rates and with marked accumulation of cholesterol [Parthasarathy et al., J. Clin. Invest. 77,641 (1986)]. It is therefore desirable to provide methods of inhibiting LDL lipid peroxidation in a patient in need thereof.
Elevated cholesterol levels are associated with a number of disease states, including restenosis, angina, cerebral atherosclerosis, and xanthoma. It is desirable to provide a method for reducing plasma cholesterol in patients with, or at risk of developing, restenosis, angina, cerebral arteriosclerosis, xanthoma, and other disease states associated with elevated cholesterol levels.
Since it has been determined that hypercholesterolemia is due to elevated LDL (hyperlipidemia), the lowering of LDL levels by dietary therapy is attempted. There are several drug classes that are commonly used to lower LDL levels, including bile acid sequestrants, nicotinic acid (niacin), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. Probucol and the fibrate derivatives are sometimes used as adjunctive therapy, usually in combination with other medications. The HMG CoA reductase inhibitors have been termed statins or vastatins. Statins are among the most effective agents currently on the market for hypercholesterolemia, and include pravastatin (Pravchol, Bristol Myers Squibb), atorvastatin (Warner Lambert/Pfizer), simvastatin (Zocor, Merck), lovastatin (Mevacor, Merck), and fluvastatin (Lescol).
Evidence suggests that the atherogenic effects of low density lipoprotein (LDL) may be in part mediated through its oxidative modification. Probucol has been shown to possess potent antioxidant properties and to block oxidative modification of LDL. Consistent with these findings, probucol has been shown to actually slow the progression of atherosclerosis in LDL receptor-deficient rabbits as discussed in Carew et al. Proc. Natl. Acad. Sci. U.S.A. 84:7725-7729 (1987). Most likely, probucol is effective because it is highly lipid soluble and is transported by lipoproteins, thus protecting them against oxidative damage.
Probucol is chemically related to the widely used food additives 2,[3]-tert-butyl-4-hydroxyanisole (BHA) and 2,6-di-tert-butyl-4-methyl phenol (BHT). Its fill chemical name is 4,4xe2x80x2-(isopropylidenedithio) bis(2,6-di-tert-butylphenol).
Probucol is used primarily to lower serum cholesterol levels in hypercholesterolemic patients. Probucol is commonly administered in the form of tablets available under the trademark Lorelco(trademark). Unfortunately, probucol is almost insoluble in water and therefore cannot be injected intravenously. In fact, probucol is difficult for cells to absorb in vitro because of its poor miscibility in buffers and media for cell culture. Solid probucol is poorly absorbed into the blood, and is excreted in substantially unchanged form. Further, the tablet form of probucol is absorbed at significantly different rates and in different amounts by different patients. In one study (Heeg et al., Plasma Levels of Probucol in Man After Single and Repeated Oral Doses, La Nouvelle Presse Medicale, 9:2990-2994 (1980)), peak levels of probucol in sera were found to differ by as much as a factor of 20 from patient to patient. In another study, Kazuya et al. J. Lipid Res. 32; 197-204 (1991) observed an incorporation of less than about 1 xcexcg of probucol/106 cells when endothelial cells are incubated for 24 h with 50 xcexcM probucol.
U.S. Pat. No. 5,262,439 to Parthasarathy discloses analogs of probucol with increased water solubility in which one or both of the hydroxyl groups are replaced with ester groups that increase the water solubility of the compound. In one embodiment, the derivative is selected from the group consisting of a mono- or di- probucol ester of succinic acid, glutaric acid, adipic acid, seberic acid, sebacic acid, azelaic acid, or maleic acid. In another embodiment, the probucol derivative is a mono- or di- ester in which the ester contains an alkyl or alkenyl group that contains a functionality selected from the group consisting of a carboxylic acid group, amine group, salt of an amine group, amide groups, amide groups, and aldehyde groups.
A series of French patents disclose that certain probucol derivatives are hypocholesterolemic and hypolipemic agents: Fr 2168137 (bis 4-hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxy alkanoic esters of probucol); Fr 2140769 (benzofuryloxyalkanoic acid derivatives of probucol); Fr 2134810 (bis-(3-alkyl-5-t-alkyl-4-thiazole-5-carboxy)phenylthio)alkanes; FR 2133024 (bis-(4-nicotinoyloxyphenylthio)propanes; and Fr 2130975 (bis(4-(phenoxyalkanoyloxy)-phenylthio)alkanes).
U.S. Pat. No. 5,155,250 to Parker, et al. discloses that 2,6-dialkyl-4-silylphenols are antiatherosclerotic agents. The same compounds are disclosed as serum cholesterol lowering agents in PCT Publication No. WO 95/15760, published on Jun. 15, 1995. U.S. Pat. No. 5,608,095 to Parker, et al. discloses that alkylated-4-silyl-phenols inhibit the peroxidation of LDL, lower plasma cholesterol, and inhibit the expression of VCAM-1, and thus are useful in the treatment of atherosclerosis.
A series of European patent applications and to Shionogi Seiyaku Kabushiki Kaisha disclose phenolic thioethers for use in treating arteriosclerosis. European Patent Application No. 348 203 discloses phenolic thioethers which inhibit the denaturation of LDL and the incorporation of LDL by macrophages. The compounds are useful as anti-arteriosclerosis agents. Hydroxamic acid derivatives of these compounds are disclosed in European Patent Application No. 405 788 and are useful for the treatment of arteriosclerosis, ulcer, inflammation and allergy. Carbamoyl and cyano derivatives of the phenolic thioethers are disclosed in U.S. Pat. No. 4,954,514 to Kita, et al.
U.S. Pat. No. 4,752,616 to Hall, et al., disclose arylthioalkylphenylcarboxylic acids for the treatment of thrombotic disease. The compounds disclosed are useful as platelet aggregation inhibitors for the treatment of coronary or cerebral thromboses and the inhibition of bronchoconstriction, among others.
A series of patents to Adir et Compagnie disclose substituted phenoxyisobutyric acids and esters useful as antioxidants and hypolipaemic agents. This series includes U.S. Pat. Nos. 5,206,247 and 5,627,205 to Regnier, et al. (which corresponds to European Patent Application No. 621 255) and European Patent Application No. 763 527.
WO97/15546 to Nippon Shinyaku Co. Ltd. discloses carboxylic acid derivatives for the treatment of arterial sclerosis, ischemic heart diseases, cerebral infarction and post PTCA restenosis.
The Dow Chemical Company is the assignee of patents to hypolipidemic 2-(3,5-di-tert-butyl-4-hydroxyphenyl)thio carboxamides. For example, U.S. Pat. Nos. 4,029,812, 4,076,841 and 4,078,084 to Wagner, et al., disclose these compounds for reducing blood serum lipids, especially cholesterol and triglyceride levels.
Given that cardiovascular disease is currently the leading cause of death in the United States, and ninety percent of cardiovascular disease is presently diagnosed as atherosclerosis, there is a strong need to identify new methods and pharmaceutical agents for its treatment. Important to this goal is the identification and manipulation of the specific oxidized biological compounds that act as selective regulators of the expression of mediators of the inflammatory process, and in particular, VCAM-1. A more general goal is to identify selective methods for suppressing the expression of redox sensitive genes or activating redox sensitive genes that are suppressed.
It is therefore an object of the present invention to provide new compounds, compositions and methods for the treatment of cardiovascular and inflammatory diseases.
It is still another object of the present invention to provide new compounds and compositions which are useful as inhibitors of LDL lipid peroxidation.
It is still another object of the present invention to provide new compounds and compositions which are useful as antiatherosclerotic agents.
It is still another object of the present invention to provide new compounds and compositions which are useful as LDL lipid lowering agents.
It is still another object of the present invention to provide new compounds, compositions and methods for selectively inhibiting the expression of VCAM-1.
It is still another object of the present invention to provide a method for the treatment of a disease that is mediated by the expression or suppression of a redox sensitive gene, for example MCP-1, IL-6 and thrombin receptor.
The present invention provides a compound, composition and method for inhibiting the expression of VCAM-1, and thus can be used in the treatment of a disease mediated by VCAM-1, which includes administering a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. The compounds of formula (I) are 
wherein
X is 0, S, SO, SO2, CH2, or NH;
Spacer is a group selected from the group consisting of xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94(CH2) nxe2x80x94Nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2O)xe2x80x94, xe2x80x94(OCH2)xe2x80x94, xe2x80x94(SCH2)xe2x80x94, xe2x80x94(CH2S), -(aryl-O)xe2x80x94, xe2x80x94(O-aryl)-, -(alkyl-O)xe2x80x94, xe2x80x94(O-alkyl)-;
n is 0,1,2,3,4,5,6,7,8,9, or 10;
Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylthioalkyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfinylalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylsulfonylalkyl, NH2, NHR, NR2, SO2xe2x80x94OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH2, C(O)NHR, C(O)NR2, SO2NH2, SO2NHR, SO2NR2;
R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members;
R1 and R2 are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R1 or R2 groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy;
R3 and R4 are independently any group that does not otherwise adversely affect the desired properties of the molecule, including H, halogen, or R1.
The compound of formula (II) has the following structure 
wherein
Ra, Rb, Rc, and Rd are independently any group that does not otherwise adversely affect the desired properties of the molecule, including hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the Ra, Rb, Rc, and Rd groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;
Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, xe2x80x94(CH2)xe2x80x94Re, xe2x80x94C(O)xe2x80x94Rg, and xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Rh, wherein (a) when each of Ra, Rb, Rc, and Rd are t-butyl, Z cannot be hydrogen and (b) when each of Ra, Rb, Rc, and Rd are t-butyl, Z cannot be the residue of succinic acid;
Re is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, xe2x80x94CH(OH)Rk, hydroxy, C(O)NH2, C(O)NHR, C(O)NR2;
Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
Rh is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, xe2x80x94CH(OH)Rk, hydroxy, O-phosphate, C(O)NH2, C(O)NHR, C(O)NR2 and pharmaceutically acceptable salts thereof;
Or, in an alternative embodiment, Re, Rg, and Rh can independently be a substituent which improves the water solubility of the compound, including, but not limited to C(O)xe2x80x94spacer-SO3H, wherein spacer is as defined above, C(O)-spacer-SO3M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)xe2x80x94spacer-PO3H2, C(O)-spacer-PO3M2, C(O)-spacer-PO3HM, C(O)-spacer-PO4H, C(O)-spacer-PO4M, SO3M, -PO3H2, -PO3M2, -PO3HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)-spacer-[O(C1-3 alkyl)p]n, wherein n is as defined above and p is 1, 2, or 3,-[O(C1-3alkyl)p]n, carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl.
The present invention generally provides a method for treating cardiovascular and inflammatory disorders in a patient in need thereof comprising administering to said patient an effective amount of a compound of formula (I) or formula (II).
The present invention further provides a method of inhibiting the peroxidation of LDL lipid in a patient in need thereof comprising administering to said patient an effective antioxidant amount of a compound of formula (I) or formula (II).
In an alternative embodiment, a method is provided for suppressing the expression of a redox-sensitive gene or activating a gene that is suppressed through a redox-sensitive pathway, that includes administering an effective amount to prevent the oxidation of the oxidized signal, and typically, the oxidation of a PUFA of a compound of formula (I) or formula (II). Representative redox-sensitive genes that are involved in the presentation of an immune response include, but are not limited to, those expressing cytokines involved in initiating the immune response (e.g., IL-1xcex2), chemoattractants that promote the migration of inflammatory cells to a point of injury (e.g., MCP-1), growth factors (e.g., IL-6 and the thrombin receptor), and adhesion molecules (e.g., VCAM-1 and E-selectin).
The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of C1 to C10, and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
The term lower alkyl, as used herein, and unless otherwise specified, refers to a C1 to C5 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group.
Likewise the term alkylene refers to a saturated hydrocarbyldiyl radical of straight or branched configuration made up of from one to ten carbon atoms. Included within the scope of this term are methylene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, 1,4-butane-diyl and the like. The alkylene group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
The term xe2x80x9cxe2x80x94CH2)nxe2x80x94xe2x80x9d represents a saturated hydrocarbyldiyl radical of straight chain configuration. The term xe2x80x9cnxe2x80x9d is defined as 0-10. The moiety xe2x80x9cxe2x80x94(CH2)nxe2x80x94xe2x80x9d thus represents a bond (i.e., when n=0), methylene, 1,2-ethanediyl or 1,3-propanediyl, etc.
The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The term aralkyl, as used herein, and unless otherwise specified, refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above. The term alkaryl, as used herein, and unless otherwise specified, refers to an alkyl group as defind above linked to the molecule through an aryl group as defined above. In each of these groups, the alkyl group can be optionally substituted as describe above and the aryl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. Specifically included within the scope of the term aryl are phenyl; naphthyl; phenylmethyl; phenylethyl; 3,4,5-trihydroxyphenyl; 3,4,5-trimethoxyphenyl; 3,4,5-triethoxyphenyl; 4-chlorophenyl; 4-methylphenyl; 3,5-di-tertiarybutyl-4-hydroxyphenyl; 4-fluorophenyl; 4-chloro-1-naphthyl; 2-methyl-1-naphthylmethyl; 2-naphthylmethyl; 4-chlorophenylmethyl; 4-tertiarybutylphenyl; 4-tertiarybutylphenylmethyl and the like.
The term xe2x80x9cprotectedxe2x80x9d as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
The term halo, as used herein, includes chloro, bromo, iodo, and fluoro.
The term alkoxy, as used herein, and unless otherwise specified, refers to a moiety of the structure xe2x80x94Oxe2x80x94alkyl, wherein alkyl is as defined above.
The term acyl, as used herein, refers to a group of the formula C(O)Rxe2x80x2, wherein Rxe2x80x2 is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups are as defined above.
As used herein, the term polyunsaturated fatty acid (PUFA) refers to a fatty acid (typically C8 to C24) that has at least two alkenyl bonds, and includes but is not limited to linoleic (C18xcex949,12), linolenic (C18xcex946,9,12), arachidonic (C20xcex948,11,14) acids.
The term oxidized polyunsaturated fatty acid (ox-PUFA) refers to an unsaturated fatty acid in which at least on of the alkenyl bonds has been converted to a hydroperoxide. Nonlimiting examples are 13-HPODE and 15-HPETE.
The term pharmaceutically acceptable salts or complexes refers to salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological effects. Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalcturonic acid; (b) base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc tannate salt or the like. Also included in this definition are pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula xe2x80x94NR+Axe2x88x92, wherien R is as defined above and A is a counterion, including chloride, bromide, iodide, xe2x80x94O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
Diseases mediated by the VCAM-1 include, but are not limited to atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, small artery disease, and other cardiovascular diseases, as well as noncardiovascular inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis and psoriasis.
In one embodiment, the invention is a method for treating a disease mediated by the expression of VCAM-1 comprising administering a compound of the formula 
wherein
X is O, S, SO, SO2, CH2, or NH;
Spacer is a group selected from the group consisting of xe2x80x94(CH2)n,xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94(CH2)nxe2x80x94Nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2O)xe2x80x94, xe2x80x94(OCH2)xe2x80x94, xe2x80x94(SCH2)xe2x80x94, xe2x80x94(CH2Sxe2x80x94), -(aryl-O)xe2x80x94, xe2x80x94(O-aryl)-, -(alkyl-O)xe2x80x94, xe2x80x94(O-alkyl)-;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, NH2, NHR, NR2, SO2xe2x80x94OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH2, C(O)NHR, C(O)NR2;
R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members;
R1 and R2 are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl,-substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R1 or R2 groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy;
R3 and R4 are independently any group that does not otherwise adversely affect the desired properties of the molecule, including H, halogen, or R1.
Preferred compounds of the present invention include compounds of formula (I) wherein
X is S, SO or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nCOxe2x80x94; n is 0-10; Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH2, NHR, NR2, alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched or cyclic C1-10 alkyl; R3 and R4 are independently hydrogen, halogen or R1.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH2, NHR, NR2, alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently straight chained, branched or cyclic C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is aryl; aryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, xe2x80x94(CH2)mxe2x80x94OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; NH2; NHR; NR2; straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO2OH, COOH or COOR; and OCOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is aryl; aryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, xe2x80x94(CH2)mxe2x80x94OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, xe2x80x94(CH2)nxe2x80x94OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkenyl, alkynyl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, xe2x80x94(CH2)mxe2x80x94OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkenyl, alkynyl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; the R group may be further substituted by alkyl, alkyl-COOH, alkyl-COOalkyl, or alkyl-COOaryl; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, xe2x80x94(CH2)mxe2x80x94OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkenyl, alkynyl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, xe2x80x94(CH2)mxe2x80x94OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl, halo, nitro, hydroxy, COOH, COOR, CONH2, CONHR, CONR2, xe2x80x94(CH2)nxe2x80x94OH wherein m is 0-10, haloalkyl, mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group, SO2OH, SO2NH2, SO2NHR, SO2NR2, or OCOR; R is alkyl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, or nitro-substituted furanyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR, R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94; n is 0-10; Y is heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is heteroaryl; heteroaryl which is mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is isoxazolyl or furanyl which may be optionally substituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is isoxazolyl which may be optionally substituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is furanyl which may be optionally substituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl, CH2NH2, CH2NHR, CH2NR2, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is NH2, NHR or NR2; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is NH2, NHR or NR2; R is alkyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94; n is 0-10; Y is NH2, NHR or NR2; R is alkyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is NH2, NHR or NR2; R is alkyl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO2OH, COOH or COOR; and OCOR; R is alkyl, alkenyl, alkynyl, and aryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO2OH, COOH or COOR; and OCOR; R is alkyl or two adjacent R groups may combine to form a ring of 5 to 7 members; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR, SO2OH, COOH; or COOR; R is alkyl; R1 and R2 are independently C1-5 allyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is selected from the group consisting of straight chained, branched or cyclic alkyl; straight chained, branched, or cyclic alkyl substituted by OCOR; R is alkyl; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is OCOR; R is alkyl; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94; n is 0-10; Y is OCOR; R is alkyl; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Another preferred embodiment of the present invention includes compounds of formula (I) wherein X is S, SO, or SO2; Spacer is xe2x80x94(CH2)nxe2x80x94COxe2x80x94; n is 0-10; Y is OCOR; R is alkyl; R1 and R2 are independently C1-5 alkyl; R3 and R4 are independently H.
Examples of the present invention include compounds of formula (I) defined as follows:
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer-CH2xe2x80x94; Y=4-carboxymethylphenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-nitrophenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94(CH2)2xe2x80x94; Y=4-nitrophenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer-CH2xe2x80x94; Y=2-carboxyethyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer-CH2xe2x80x94; Y=3,5-di-t-butyl-4-carboxypropanoyloxy;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-carboxyphenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=1-acetyloxy-1-methylethyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=3-nitrophenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=2,4-dinitrophenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-trifluoromethylphenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=2-carboxyfuranyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-(N,N-dimethyl)sulfonamidophenyl;
X=SO; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-nitrophenyl;
X=SO2; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-nitrophenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-acetyloxyphenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-methylphenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-fluorophenyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=ethylsulfonic acid;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=2-dimethylaminomethyl;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacerxe2x80x94(CH2)3xe2x80x94; Y=dimethylamino;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94(CH2)5xe2x80x94; Y=acetyloxy;
X=S; R1=t-butyl; R2=t-butyl; R3=H; R4=H; Spacer=xe2x80x94CH2xe2x80x94; Y=4-(2-hydroxy)ethylphenyl.
In another embodiment of the invention, there is provided a compound of formula (II) and a method for treating a disease mediated by the expression of VCAM-1 comprising administering an effective amount of a compound of formula (II): 
wherein
Ra, Rb, Rc, and Rd are independently hydrogen, straight chained, branched (for example, tert-butyl), or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the Ra, Rb, Rc, and Rd groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;
Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, xe2x80x94(CH2)xe2x80x94Re, xe2x80x94C(O)xe2x80x94Rg, and xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Rh, wherein (a) when each of Ra, Rb, Rc, and Rd are t-butyl, Z cannot be hydrogen and (b) when each of Ra, Rb, Rc, and Rd are t-butyl, Z cannot be the residue of succinic acid;
Re is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, xe2x80x94CH(OH)Rk, hydroxy, C(O)NH2, C(O)NHR, C(O)NR2;
Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
Rh is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH2, NHR, NR2, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, xe2x80x94CH(OH)Rk, hydroxy, O-phosphate, C(O)NH2, C(O)NHR, C(O)NR2 and pharmaceutically acceptable salts thereof;
or, in an alternative embodiment, Re, Rg, and Rh can independently be a substituent which improves the water solubility of the compound, including, but not limited to C(O)-spacer-SO3H, wherein spacer is as defined above, C(O)-spacer-SO3M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)-spacer-PO3H2, C(O)-spacer-PO3M2, C(O)-spacer-PO3HM, C(O)-spacer-PO4H, C(O)-spacer-PO4M, SO3M, xe2x80x94PO3H2, xe2x80x94PO3M2, xe2x80x94PO3HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)-spacer-[O(C1-3 alkyl)p]n, wherein n is as defined above and p is 1, 2, or 3, xe2x80x94[O(C1-3 alkyl)p]n, carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl.
Substitutents on the groups defined above are selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, halo, nitro, amino, alkylamino, dialkylamino, carboxy, aryl, heteroaryl, COOR, CONH2, CONHR, CONR2, haloalkyl, alkoxyalkyl, mono- or polyhydroxyalkyl, CH2xe2x80x94OR, CH2xe2x80x94OH, OCOR, O-phosphate, SO2xe2x80x94NH2, SO2xe2x80x94NHR, SO2xe2x80x94NR2.
A preferred embodiment of the present invention includes compounds of formula (II) wherein Ra, Rb, Rc, and Rd are independently hydrogen or straight chained, branched, or cyclic C1-10 alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, xe2x80x94(CH2)xe2x80x94Re, xe2x80x94C(O)xe2x80x94Rg, and xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Rh, and pharmaceutically acceptable salts thereof Another preferred embodiment of the present invention includes compounds of formula (II) wherein Ra, Rb, Rc, and Rd are independently hydrogen or straight chained, branched, or cyclic C1-5 alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, xe2x80x94(CH2)xe2x80x94Re, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Rh, and pharmaceutically acceptable salts thereof.
Another preferred embodiment of the present invention includes compounds of formula (II) wherein Ra, Rb, Rc, and Rd are independently hydrogen or straight chained, branched, or cyclic C1-5 alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, xe2x80x94CH2-aryl substituted alkynyl, a carbohydrate group, xe2x80x94CH2xe2x80x94NR2, xe2x80x94CH2-alkoxy, xe2x80x94CH2xe2x80x94CHOH, xe2x80x94CH2-substituted aryl, xe2x80x94CH2-alkyl, xe2x80x94CH2-substituted alkyl, xe2x80x94CH2-OCO-alkyl, xe2x80x94CH2xe2x80x94OCO-substituted alkyl, xe2x80x94CH2xe2x80x94COOR, xe2x80x94CH2xe2x80x94CH(OH)CH2NHCH2COOR, xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94substituted oxiranyl (wherein the substituent is selected from the group consisting of hydrogen, CH2OH, CH2OCHOH-oxiranyl), xe2x80x94CO-aryl, xe2x80x94CO-substituted aryl, xe2x80x94CO-heteroaryl, xe2x80x94CO-substituted heteroaryl, xe2x80x94COxe2x80x94(CH2)nxe2x80x94COOR, xe2x80x94COxe2x80x94(CH2)nxe2x80x94OH, xe2x80x94COxe2x80x94(CH2)nxe2x80x94O-phosphate, COxe2x80x94(CH2)nxe2x80x94COxe2x80x94NR2, xe2x80x94COxe2x80x94(CH2)n-aryl, xe2x80x94COxe2x80x94(CH2)n-substituted aryl, xe2x80x94COxe2x80x94(CH2)n-heteroaryl, xe2x80x94COxe2x80x94(CH2)n-substituted heteroaryl, xe2x80x94COxe2x80x94(CH2)nxe2x80x94CONH(CH2)COOR, xe2x80x94COxe2x80x94(CH2)nxe2x80x94CON((CH2)COOR)2, monosaccharides, and cyclic monosaccharides, and pharmaceutically acceptable salts thereof.
Another preferred embodiment of the present invention includes compounds of formula (II) wherein Ra, Rb, Rc, and Rd are independently hydrogen or straight chained, branched, or cyclic C1-5 alkyl; Z is selected from the group consisting of hydrogen, alkyl, hydroxy alkyl, polyhydroxy alkyl, alkenyl, hydroxy alkenyl, acyl-substituted alkenyl, alkoxy alkyl, nitrophenylalkyl, aminophenylalkyl, alkylaminophenylalkyl, dialkylaminophenylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, acyloxyalkyl, oxiranyl-substituted hydroxyalkyl, hydroxyalkyl-substituted oxiranylmethylene, oxiranyl-substituted hydroxyalkoxyalkyl oxiranylmethylene, oxiranylmethylene, carboxyalkylaminohydroxyalkyl, alkoxyhydroxyalkyl, glucopyranosyl, galactopyranosyl, N,N-diacylalkylaminohydroxyalkyl, carboxyalkylaminopolyhydroxyalkyl, (amino)(carboxy)alkylaminohydroxyalkyl, acyloxyhydroxyalkyl, polyhydroxyalkylaminohydroxyalkyl, CO-carboxyalkyl, CO-nitrofuranyl, CO-hydroxyalkyl, CO-polyhydroxyalkyl, CO-amidoalkyl, CO-aminoalkyl, CO-alkylaminoalkyl, CO-dialkylaminoalkyl, CO-acylalkyl, CO-alkoxycarbonylalkyl, CO-tetrazolylalkyl, CO-(acyl)(amino)alkylamino, dialkoxycarbonylalkylamidoalkyl, CO-hydroxyphenyloxyphosphonoxyalkyl, or pharmaceutically acceptable salts thereof.
Examples of the present invention include compounds of formula (II) wherein:
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-nitrophenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=COxe2x80x94(CH2)2xe2x80x94COOH;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-(5-nitrofuran-2-yl);
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-carboxypropyl;
Ra=1-methylethyl, Rb=t-butyl, Rc=methyl, and Rd=methyl; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-hydroxypropanoyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=t-butylcarbonyloxymethyl;
Ra=t-butyl, Rb=t-butyl, Rc=H, and Rd=H; Z=4-aminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=H, and Rd=H; Z=3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=carboxymethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2xe2x80x94(CONH2)ethanoyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-aminomethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-(2-carboxyethyl);
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-(2-methoxycarbonylethyl);
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-aminomethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-carboxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-2-carboxyethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-ammonium methyl (chloride)
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-2-oxiranyl-ethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-hydroxymethyloxirany-2-ylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-(2-hydroxy-2-oxiranyl) ethoxyoxiran-2-ylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=oxiranylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-carboxymethylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3,4-trihydroxybutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-ethoxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3-dihydroxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=ethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-ethoxycarbonylethenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-N,N-dimethylaminophenethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-2-carboxyethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-2-carboxyethyl (L-arginine ester);
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-methoxycarbonylpropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-carboxyethenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=galactopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-(N-N-diethylamino)propyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-ethoxycarbonylethenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=carboxymethylaminocarbonylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=1,3-dicarboxypropylaminocarbonylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-(1,3-diethoxycarbonyl)propylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3-dihydroxy-4-carboxymethylaminobutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-(5-amino-5-carboxy)propylaminopropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-ethylcarbonyloxybutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=4-hydroxybutyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=glucopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-3-tetrazolylpropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=3-hydroxypropenyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CH2CONHxe2x80x94(CH2)CH(NH2)COOH;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl;
Z=CH2CONHCH(COOet)CH2CH2(COOet);
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=glucopyranosylmethyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2,3,4,5,6-pentahydroxyhexane;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-3xe2x80x94(2-hydroxyphenyloxyphosphoxy)propyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CO-2,2-dimethyl-3-hydroxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-hydroxy-3-acetoxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=2-acetoxy-3-hydroxypropyl;
Ra=t-butyl, Rb=t-butyl, Rc=t-butyl, and Rd=t-butyl; Z=CH2CH(OH)CH2NH(2,3,4,5,6-pentahydroxyhexane.
The compounds of formula (I) can be prepared by utilizing known procedures and techniques, or routine modifications thereof. A general synthetic scheme for preparing compounds of formula (I) is set forth in Scheme A, wherein all substituents, unless otherwise indicated, are previously defined.
Scheme A
The synthesis of the starting thiol, 4-mercapto-2,6-di-t-butylphenol, is described in the literature (U.S. Pat. No. 3,129,262 to Laufer, incorporated herein by reference in its entirety). The starting alkyl halides are commercially available or made from commercially available starting materials by methods known to one of ordinary skill in the art.
A quantity of the 4-mercapto-2,6-di-t-butylphenol is dissolved in ethanol to make a 0.5 M solution and treated with 1.2 equivalents of sodium hydroxide (5 N aqueous solution). After 5 minutes 1.2 equivalents of alkyl halide is added and the reaction mixture stirred at room temperature for 24 hours. The reaction is quenched with 1 N HCl to pH 7, diluted with water, extracted with ether and dried over magnesium sulfate. The product is purified by silica gel chromatography.
Starting materials for use in the general synthetic procedure outlined in Scheme A are readily available to one of ordinary skill in the art. For example, certain phenol starting materials for various compounds of formula (I), such as 2,6-di-tertiarybutyl-4-mercaptophenol, are described in U.S. Pat. No. 3,576,883, U.S. Pat. No. 3,952,064, U.S. Pat. No. 3,479,407 and in Japanese Patent Application 73-28425.
In general, a phenol of structure (I) can be prepared by dissolving the appropriate 2,6-dialkyl-4-thiophenol (or suitably protected derivatives) in alcohol, preferably in ethanol, followed by addition of a halogenated aryl compound.
The starting material, a 2,6-dialkyl-substituted thiophenol, may be protected by any of the many protecting groups known to one of ordinary skill in the art. Examples of suitable phenol protecting groups are ethers, such as methoxymethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, t-butyl and benzyl; silyl ethers, such as trimethylsilyl and 1-butyldimethylsilyl; esters, such as acetate and benzoate; carbonates, such as methylcarbonate and benzyl carbonate; as well as sulfonates, such as methane sulfonate and toluene sulfonate.
The following examples present typical syntheses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings xe2x80x9cgxe2x80x9d refers to grams; xe2x80x9cmmolxe2x80x9d refers to millimoles; xe2x80x9cmLxe2x80x9d refers to milliliters; xe2x80x9cbpxe2x80x9d refers to boiling point; xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cmm Hgxe2x80x9d refers to millimeters of mercury; xe2x80x9cmpxe2x80x9d refers to melting point; xe2x80x9cmgxe2x80x9d refers to milligrams; xe2x80x9cxcexcMxe2x80x9d refers to micromolar; xe2x80x9cxcexcgxe2x80x9d refers to micrograms.